A specific missense mutation in GTF2I occurs at high frequency in thymic epithelial tumors

Abstract

We analyzed 28 thymic epithelial tumors (TETs) using next-generation sequencing and identified a missense mutation (chromosome 7 c.74146970T>A) in GTF2I at high frequency in type A thymomas, a relatively indolent subtype. In a series of 274 TETs, we detected the GTF2I mutation in 82% of type A and 74% of type AB thymomas but rarely in the aggressive subtypes, where recurrent mutations of known cancer genes have been identified. Therefore, GTF2I mutation correlated with better survival. GTF2I β and δ isoforms were expressed in TETs, and both mutant isoforms were able to stimulate cell proliferation in vitro. Thymic carcinomas carried a higher number of mutations than thymomas (average of 43.5 and 18.4, respectively). Notably, we identified recurrent mutations of known cancer genes, including TP53, CYLD, CDKN2A, BAP1 and PBRM1, in thymic carcinomas. These findings will complement the diagnostic assessment of these tumors and also facilitate development of a molecular classification and assessment of prognosis and treatment strategies.

Genome-wide targeting of the epigenetic regulatory protein CTCF to gene promoters by the transcription factor TFII-I

“…S6B). Recently, it has been shown that cancer-specific mutations of TFII-I increase cell proliferation (46). Though it remains to be proven, it is also possible that loss of function GTF2i mutations may disrupt metabolic homeostasis to provide a survival advantage that is distinct from its previously described role in proliferation (47,48).…”

Evolution of Classification of Thymic Epithelial Tumors in the Era of Dr Thomas V. Colby

“…More recently, GTF2I missense mutations have been found in types A and AB thymomas and less commonly in types B1, B2, and B3 thymomas. 64 These mutations were rather uncommon in thymic carcinoma (Table 9).…”

Thymome

“…50 % der Fälle AIRE(+)-Epithelzellen und Desmin(+)-Myoidzellen nachweisbar sind. Genetische Alterationen sind seltener als in B2-und B3-Thymomen [7,18], GTF2I-Mutationen kommen in 32 % der Fälle vor [21].…”

“…Genetische Alterationen sind seltener als in B3-Thymomen, überlappt aber bei Verlusten von 6q25,2-q25,3 und 3p und Zugewinnen von 1q [7,18]. Zweiundzwanzig Prozent zeigen GTF2I-Mutationen [21]. T-LBL weisen auch TdT(+), aber atypische Lymphoblasten auf, die das Keratin(+)-thymische Epithelzellnetz destru-Abb.…”

“…B3-Thymome zeigen von allen Thymomen die höchste Rate genetischer Alterationen, darunter weitgehend "B3-spezifische" Verluste von 13q, 16q und 17p und Zugewinne von 4p und 17q [7,18]. GTF2I-Mutationen kommen in 21 % der Fälle vor [21].…”